Underuse of Postoperative Radiation After Nipple-Sparing Mastectomy for Standard Radiation Indications

Purpose Nipple areola complex-sparing surgeries, such as nipple-sparing mastectomy (NSM), are increasingly used for women with early-stage breast cancer. In the postoperative setting, 2 major indications for postoperative radiation (PORT) with/without regional nodal irradiation (RNI) are: positive margins (margin+) and pathologically involved lymph nodes (pN+). The frequency of these adverse pathologic features and the rate of PORT utilization following NSM for these 2 indications are unknown. We determined the frequency of margin+ and pN+ following NSM compared with nipple-sparing lumpectomy/breast-conserving surgery [BCS] and identified trends in appropriate PORT administration for these standard indications in the NSM setting. Methods and Materials Using the National Cancer Database (NCDB), women diagnosed with cT1 to cT3,N0M0 invasive carcinoma between 2004 and 2017 who underwent NSM were compared with those who underwent BCS (with nipple preservation). The frequencies of margin+ and pN+ by surgical subtype and use of PORT with/without RNI were assessed by cohort to determine if the type of surgery was associated with radiation delivery. Overall survival between the 2 cohorts was also compared. We performed univariable/multivariable logistic and Cox regression with ORs to control for confounders. Results Of 624,075 women included, 611,907 underwent BCS, and 12,168 underwent NSM. The surgical margin+ rate was significantly higher for NSM at 4.5% (n = 544) than for BCS at 3.7% (n = 22,449) (P < .001) and remained significant on multivariable analysis (MVA; OR, 1.13; CI, 1.03-1.25; P = .012). Use of PORT for margins+ was significantly lower by MVA after NSM (OR, 0.07; CI, 0.06-0.09; P < .001). Similarly, pN+ rate was significantly higher for NSM at 22.5% (n = 2740) versus BCS at 13.5% (n = 82,288) (P < .001), retaining significance on MVA (OR, 1.12; CI, 1.06-1.19; P < .001). For pN+ undergoing NSM, PORT with RNI was delivered significantly less often on MVA (OR, 0.73; CI, 0.67-0.81; P < .001). Neither high-risk subgroup had differences in overall survival on MVA. Conclusions NSM is associated with a higher rate of margin+ and pN+ compared with BCS. Radiation is underused after NSM for these standard indications. Our results highlight the need to further refine patient selection for NSM and the importance of communicating the higher potential for adverse pathologic features (and thus, the potential need for radiation) to patients undergoing NSM.


Introduction
For women with early-stage breast cancer, preservation of the nipple-areolar complex (NAC) and skin flap overlying the glandular breast tissue results in better patient-reported cosmetic and functional outcomes than if these structures are sacrificed. 1 As a result, surgical techniques that spare the NAC have increased in use. 2 Sparing of the NAC is generally very common after a breast conservation procedure because it aligns with the surgical foundation of preserving the affected breast while optimizing cosmesis (eg, lumpectomy/breast-conserving surgery [BCS]). 3,4Similarly, in the mastectomy setting, the use of nipple-sparing techniques (eg, nipple-sparing mastectomy [NSM]) offers the patient a better chance for preserving body image and nipple function, thus enhancing quality of life. 1,5he indications for radiation after definitive surgery with either BCS or mastectomy are well delineated. 6][9][10] In contrast, after mastectomy, the presumption is that the at-risk breast tissue has been removed.Thus, most patients do not require adjuvant radiation, with postoperative radiation therapy (PORT +/À RNI) typically reserved for patients with higher-risk features such as surgical margin positivity, pathologic lymph node involvement, or large tumor size (>5 cm). 11,124][15] Given the association between PORT and potential postoperative complications in NSM patients, 16,17 particularly NAC necrosis or compromised cosmetic outcome, reluctance for PORT delivery for patients undergoing NSM would be understandable. .We hypothesize that PORT is underused in the NSM setting, and to better understand these patterns of care, we used the National Cancer Database (NCDB) to investigate 2 standard indications for PORT (positive margin [margin+] status and pathologic node positivity[pN+]) in early-stage breast cancer patients undergoing NSM.We compared a larger cohort of NSM patients with BCS patients to assess whether the use of PORT for these 2 indications was equivalent.

Methods and Materials
We used the 2020 release of the NCDB to assess patterns of care among patients with early-stage, clinically node-negative breast cancer.A joint project of the American Cancer Society and the Commission on Cancer of the American College of Surgeons, the NCDB, is a nationwide, facility-based, comprehensive clinical surveillance resource oncology data set that currently captures 72% of all newly diagnosed malignancies in the United States annually. 18Patients without prior cancer history were included if they had a preoperative biopsy histologically confirming breast cancer diagnosed with cT1 to cT3, cN0M0 invasive ductal or lobular carcinoma between the years 2004 and 2017; all patients who underwent definitive NSM or BCS resection (with exclusion of those patients who had nipple-areolar removal with local excision) with known final margin status were included.A margin+ was defined as gross or microscopic tumor present at the final surgical margin, including re-resection margins.
Descriptive statistics with x 2 testing, univariable analysis and multivariable analysis (MVA) using logistic regression with OR, and multivariable Cox proportion hazards regression analysis (with 95% CI) were performed using Stata software (v13.1) to determine final margin+ or pathologic node involvement (pN+) rates for each surgical cohort (NSM vs BCS) to determine whether PORT +/À RNI receipt varied by type of surgery.Overall survival (OS) for patients with margin+ or pN+ was analyzed as a function of surgical procedure performed to determine if there were any long-term survival differences.To control for observable biases between treatment cohorts, regressions incorporating disease and patient characteristics hypothesized to contribute to margin positivity, nodal positivity, adjuvant radiation delivery, and survival were performed.These variables included age, year of diagnosis, comorbidity burden (Charlson-Deyo comorbidity index), race/ethnicity (White non-Hispanic, Black, White Hispanic, and other), insurance status, academic versus nonacademic treatment center, median annual income in a patient's area of residence (≥$63,000 and <$63,000), distance from a treatment center (≥20 miles and <20 miles), clinical tumor size, neoadjuvant systemic therapy, histologic grade, ER, PR, human epidermal growth factor receptor 2 status, and genomic risk score (high risk, low risk, and not performed).For adjuvant radiation therapy delivery and survival, variables for pathologic tumor size and nodal stage, extent of lymph node evaluation, and adjuvant therapy receipt were also included in regression models.All clinicalpathologic parameters that met a significance threshold of P < .10 on univariable logistic regression were included in the respective multivariable model.
An additional sensitivity analysis was performed for patients who received diagnoses after January 1, 2015, in order to determine if the publication of 2 large randomized phase 3 trials (both accruing majority pN+ patients and demonstrating a disease-free survival benefit associated with adjuvant radiation delivery) 19,20 affected patterns of postoperative radiation delivery.The study was granted exemption by the institutional review board.
When assessing only patients who received diagnoses after January 1, 2015, there was a significant increase in PORT use after NSM for patients with pN+, with 34.6% of patients who received diagnoses before this date receiving RNI (N = 339), compared with 41.9% of those who  Abbreviations: BCS = breast-conserving surgery; ER = estrogen receptor; HER-2 = human epidermal growth factor receptor 2; NSM = nipple-sparing mastectomy; PR = progesterone receptor.

Discussion
In this study, we have used the NCDB to analyze the use of PORT+/−RNI in the setting of NSM for 2 standard indications for postoperative radiation (margin+ and pathologic node positivity).We chose to compare NSM with BCS (instead of simple or modified radical mastectomy) to reduce the selection bias inherent to this population of patients based on the following: (1) our assumption that patients undergoing NSM would be a selected group of early-stage, young(er), and lower-risk cohort and would be less likely to have confounding factors for omission of PORT (ie, multiple comorbidities or elderly age); (2) the early-stage, breast conservation patients with nipple-sparing would be more similar to the NSM cohort than simple mastectomy cohort; and (3) our exploratory analysis (not shown but available) confirmed that the use of mastectomy as a comparison arm with NSM had a higher degree of variability in age and significantly more high-risk features than the comparison of NSM with BCS.Our findings suggest that NSM is associated with higher rates of final surgical margin+ and pN+ disease compared with BCS.Furthermore, patients undergoing NSM were found to have received PORT+/−RNI significantly less often than BCS for the standard indications of margin+ and macroscopic node-positive disease.
It was notable that the final margin+ rates were higher among patients who underwent NSM than BCS.We acknowledge that this finding is surprising on its surface given that NSM necessitates excision of more breast tissue than BCS.One explanation may be that patients undergoing NSM had larger tumors; however, our subset analysis of even the cohort with the smallest tumor size (cT1) suggests that the margin+ rate is higher in the NSM cohort than in the BCS cohort.This finding is likely due to the relative increase in difficulty in performing a re-excision after a margin+ following NSM, when immediate reconstruction is performed, in comparison with a margin+ after BCS, which generally has a localizable tumor bed with potential for additional tissue to be removed.Alternatively, this finding may be due to reluctance perform a nipple-sacrificing technique in the setting of NAC involvement, given the time and energy invested in the nipple-sparing procedure.Finally, the lack of clearcut guidelines delineating the clinical scenarios when NSM is contraindicated may result in surgeons offering/performing NSM more often for patients with higher risks of mar-gin+, with less referrals for PORT.Similarly, the rate of pN+ disease was significantly higher in the NSM compared with the BCS cohort, and among these pN+, NSM patients were found to be less likely to receive PORT + RNI.Although future data, potential biologic assays or genomic risk scores offer promise to identify subsets of pN+ cohorts in whom PORT can be safely omitted , at present, this practice would be in opposition to guideline recommendations on appropriate adjuvant therapy.Together, these findings suggest that the patient selection for NSM needs additional refinement.Furthermore, our findings suggest that current standard indications/guidelines for PORT are not currently being appropriately utilized after NSM.The underuse of PORT was also evident in the subset of NSM patients with gross macrometastasis (micrometastatic disease excluded) and, remarkably, was also underused in the clinical situation where axillary dissection was omitted in NSM patients with macrometastatic disease on sentinel node biopsy alone.This underutilization of PORT+/−RNI, despite clearcut indications (whether intentional or unintentional), may be due to concerns for cosmetic complications including NAC loss/necrosis or reluctance of Table 2 Reason for no PORT in the margin positive and pathologic node-positive setting."Not part of the first line of therapy" indicates that multiple options were offered and the patient selected treatment that did not include radiation of the primary site, or if the option of "no treatment" was accepted by the patient Abbreviations: BCS = breast-conserving surgery; ER = estrogen receptor; Her2 = human epidermal growth factor receptor 2; NSM = nipple-sparing mastectomy.
Advances in Radiation Oncology: September 2024 Underuse of PORT following NSM surgeons or patients to pursue additional local-regional treatment after such an extensive procedure as NSM, with the perception of low risk of recurrence.Therefore, our findings highlight the need to further refine patient selection for NSM so that margin+ rates and node positivity in patients undergoing NSM are reduced, thus reducing the need for PORT +/À RNI.It is also important to reemphasize to patients considering treatment options that (nipple-sparing) lumpectomy and radiation provide similar/superior cosmetic and functional outcomes 21 as NSM without any differences in survival, ultimately allowing for an overall lower treatment burden.Lastly, it is critical that surgeons inform patients being considered for NSM that, given the significantly higher likelihood of positive margins and potential for pathologic nodal involvement, PORT +/À RNI may be indicated in the postoperative setting.Patient presentation at multidisciplinary tumor boards with radiation oncologists, medical oncologists, and surgical oncologists may increase both proper patient selection for NSM and the proper use of PORT following NSM.We performed an exploratory analysis of patients who received diagnoses and treated after the publication of 2 pivotal radiation trials in 2015 assessing the benefit of PORT in patients and further established the benefits of PORT in the pN+ setting.Our assessment indicated that there has indeed been an increase in the uptake of PORT use after NSM for ypN+ patient since 2015.Despite this increase, our multivariate analysis suggested that NSM remains associated with a lower likelihood of receiving RNI compared with BCS among cases diagnosed after 2015.Thus, our findings suggest that even in a more contemporary patient subset, there appears to remain patterns of underutilization of PORT in pN+ patients following NSM.
Our study has several limitations.The NCDB does not capture data on local-regional recurrence or cause-specific mortality.Although generally, the primary benefit of PORT +/À RNI delivery for margin+ or pN+ disease is diminishing local-regional relapse, it is important to note that PORT+/−RNI has, in fact, been demonstrated to decrease distant recurrence and result in a small, but statistically significant, breast cancer-specific survival benefit. 7,22Thus, underuse of PORT for these clinical scenarios that have the potential for residual microscopic disease after NSM may have important implications on outcomes that cannot be measured by this data set.Although it is reassuring that the underuse of PORT does not appear to result in significant treatment-related differences or compromise OS, it is likely that most recurrences experienced in these cohorts were local-regional in nature and theoretically may be salvaged with additional surgery, radiation, and systemic therapy, hence ultimately resulting in similar long-term survival outcomes.Furthermore, any differences in survival outcomes from radiation are typically not apparent until 15 years or more after treatment, and given the relatively short median follow-up of this cohort, we would not anticipate being able to demonstrate differences in survival outcomes based on the benefits of radiation alone.The NCDB does not capture all pathologic details about a tumor specimen.Margin status is reported as negative, microscopically positive, or macroscopically positive; whether a microscopic margin was focally, extensively, or multifocally positive is not reported.Although current guidelines strongly recommend radiation in the setting of any margin+, whether physicians felt more comfortable omitting radiation in the focally margin+ setting cannot be determined.Lastly, it is noteworthy that the most common reason for omission of PORT among margin-or node-positive NSM patients was that "radiation was not felt to be indicated" (by the provider) and, in fact, the proportion of patients refusing PORT or with contraindications for PORT was greater for BCS than for NSM in these settings, further suggesting that underuse of radiation following NSM is more a function of provider preference than patient-related factors.

Conclusions
In summary, our analysis of PORT use following NSM for 2 commonly accepted standard indications (margin positivity and pathologic node positivity) suggests that PORT is being underused compared with BCS.Although it is understandable that providers may be less likely to refer an NSM patient for radiation because of the higher possible risk of NAC necrosis and adverse functional or cosmetic outcomes associated with radiation, the higher rates of margin+ and pN+ disease without PORT +/À RNI delivery is alarming.Although this data set is limited in its inability to analyze local-regional recurrence outcomes and potential differences in long-term survival outcomes, our results highlight the need to further refine patient selection for NSM.Furthermore, for those pursuing NSM, the comparable survival outcomes of NSM and BCS in early-stage breast cancer, and the higher potential for adverse pathologic features requiring PORT should be discussed with patients, so informed discussions are made and local-regional outcomes are not ultimately compromised.

Disclosures
Dr. Meena Moran is Vice Chair of the National Comprehensive Cancer Network (NCCN) Breast Panel.

Figure 1
Figure 1 Selection map for inclusion.Abbreviation: NCDB = National Cancer Database.

Table 1
Cohort characteristics of patients receiving BCS and NSM

Table 6
Multivariate analysis for regional nodal irradiation in the setting of node positivity